Hypercholesterolemia is known to be one of the prime risk factors for ischemic cardiovascular disease such as arteriosclerosis. To date, there is still no effective antihypercholesterolemic agent commercially available that has found wide patient acceptance. The bile acid sequestrants seem to be moderately effective but they must be consumed in large quantities, i.e. several grams at a time and they are not very palatable.
There are agents known, however, that are very active antihypercholesterolemic agents that function by limiting cholesterol biosynthesis by inhibiting the enzyme, HMG-CoA reductase. These agents include the natural fermentation products compactin and mevinolin and a variety of semi-synthetic and totally synthetic analogs thereof. The naturally occurring compounds and their semi-synthetic analogs have the following general structural formulae: ##STR1## wherein:
R.sup.3 is hydrogen, C.sub.1-5 alkyl or C.sub.1-5 alkyl substituted with a member of the group consisting of phenyl, dimethylamino, or acetylamino; and
R.sup.4 is: ##STR2## wherein B is ##STR3##
R.sup.5 is H or OH: and
R.sup.6 is hydrogen or methyl; and a, b, c, and d represent optional double bonds, especially where b and d represent double bonds or a, b c, and d are all single bonds; provided that where a is a double bond, B is ##STR4##
Copending U.S. patent application Ser. No. 048,136 filed May 15, 1987 discloses biosynthetic and semisynthetic analogs of mevinolin and related compounds which possess a hydroxymethyl or a carbonyloxy group of structure --CO.sub.2 R.sup.3 substituted on the 6-position of the polyhydronaphthyl moiety and wherein R.sup.4 is ##STR5## wherein
R.sup.1 is a broadly-defined acyl side chain which includes, among other groups, substituted and unsubstituted C.sub.1-10 alkyl, C.sub.1-10 alkoxy, C.sub.1-10 alkenyl, C.sub.3-8 cycloalkyl and phenyl;
R.sup.2 is CH.sub.2 OH or CO.sub.2 R.sup.3 ; and
R.sup.3 is hydrogen, 2,3-dihydroxypropyl, C.sub.1-5 alkyl, C.sub.1-5 alkyl substituted with a member of the group consisting of phenyl, dimethylamino, or acetylamino;
a, b, and c each represent single bonds or one of a, b, and c represents a double bond or both a and c represent double bonds;
Said 6-hydroxymethyl and 6-carbonyloxy derivatives of mevinolin and analogs thereof are useful in treating hypercholesterolemia. However, comparative test data indicate that the 6-hydroxymethyl mevinolin analogs have a greater HMG-CoA reductase inhibiting effect than the 6-carboxy compounds. Thus there is a real need for the conversion of the 6-carboxy substituent into a 6-hydroxymethyl substituent in a minimum number of steps and without affecting the variety of other functionalities in the compound under conversion.